Environmentally sensitive hydrogels have been to focus of extensive investigation over the past several decades. These crosslinked polymeric systems can be engineered to swell and shrink (de-swell) in response to a variety of physical, chemical, and biological stimuli. Hydrogels therefore can operate as transducers without the requirement for an on board power source. Much research and development in this area has been towards actuating systems in which a drug embedded hydrogel can be directed to swell and release its payload in response to pH, temperature, magnetic field and other stimuli. Recently, environmentally sensitive hydrogels have been integrated with micromachined and MEMS structures in order to expand their capabilities by coupling them to hard inorganic materials. An example is described by Lei et al. in “A Hydrogel Based Implantable Micromachined Transponder for Wireless Glucose Measurement,” Diabet. Technol. Therap. 2006; 8:112-22. A glucose-sensitive hydrogel was coupled to the plate of a micromachined capacitive sensor. Specifically, swelling of the glucose-sensitive hydrogel deflected the moving plate of a MEMS capacitor. The resonant frequency of a parallel LC circuit in which the capacitor was the sensing element thus changed with glucose concentration, permitting remote glucose measurement by monitoring that resonant frequency Such devices, however, require complicated fabrication processes, e.g., snug-filling of a small cavity with hydrogel. Some such sensors require being hermetically sealed against aqueous environments but still providing an electrical feedthrough. Sensors have also been developed that measure the pressure exerted by a hydrogel when it swells. Sensors have also been developed that measure temperature, pH and salt concentration, by combining a suitably sensitive hydrogel with a MEMS capacitor. Actuators have been developed that stimulate a hydrogel electromagnetically. Temperature changes generated inside the hydrogels by the electromagnetic fields, which can, e.g., heat superparamagnetic nanoparticles embedded in the hydrogel, causes swelling and shrinking of the hydrogels.
The past several decades have witnessed marked improvements in the understanding and treatment of diabetes mellitus, a disorder which affects millions in the U.S. and abroad, with increasing incidence nationally and internationally due to lifestyle changes. While acute mortality due to diabetes can be averted by regular paraprandial injections of insulin, long term morbidities due to chronic hyperglycemia (condition caused by high glucose levels) remain a challenge.
Diabetes refers to disorders in glucose homeostasis and hence energy storage and use by the body. There are two major types of diabetes. In Type I or juvenile onset diabetes, pancreatic beta cells, which normally would secrete insulin, a regulator of blood glucose level, are destroyed. Persons with Type I diabetes exhibit wide swings in blood glucose, including episodes of hyperglycemia (blood glucose too high) following meals. Over a life time, hyperglycemia can lead to degeneration of nerve, muscle, and connective tissue, with shortened life span and degraded quality of life. Blindness or loss of extremities can occur in extreme cases. Type I diabetes can be controlled by judicious injection of insulin, either through a syringe or a catheter connected to a wearable pump. Care must be taken, however, that insulin administration does not drive blood sugar level too low (hyperglycemia), as this may lead to disorientation, coma, or death. The Type I diabetic must therefore monitor his or her glucose level frequently to administer the correct amount insulin at the appropriate time.
In Type II or adult onset diabetes, insulin is not utilized properly to regulate blood glucose level. Type II diabetics cannot be treated by insulin alone, and a number of drugs have been developed to improve glucose homeostasis. Incidence of Type II diabetes has sharply increased both in the US and internationally, primarily due to consumption of unhealthy foods and sedentary lifestyle. Diet and exercise are important regulators of glucose metabolism in treating Type II diabetes, and glucose monitoring may play an increasing role by providing “on-line” feedback to the patient and caregiver regarding these behavioral aspects.
A secondary physiological consequence of diabetes is reduced control of blood pH, and diabetics exhibit so-called “acidotic” and “alkalotic” swings. Since blood pH is normally constant at pH 7.4, these swings, besides being detrimental, reveal the state of health of the diabetic. Thus, a continuous monitor of blood pH, in tandem with blood glucose level, may provide useful complementary information for evaluating treatment.
Largely due to the landmark Diabetes Control and Complications Trial (DCCT), it is widely believed that improved health and quality of life for diabetics is correlated with maintenance of blood glucose levels within relatively tight bounds. DCCT established that minimizing hyperglycemia helps forestall development of long term morbidities, which are attributed to long term hyperexposure of tissues to glucose. However, a tendency among some patients to “overinsulinize” themselves in response to hyperglycemic episodes can lead to dangerous hyperglycemic and hypoglycemic swings.
Typically, patients monitor their blood glucose intermittently using a finger stick method. However, finger sticks are uncomfortable and provide time-separated, discrete observations of blood glucose level, which changes continuously as a function of time. Indeed, based on the current method of intermittent monitoring of glucose, some of the fluctuations, including sudden hypoglycemic episodes, can be missed.
Transcutaneous glucose electrodes generally pose challenges such as infection due to the transcutaneous nature of the sensors, enzyme denaturation in enzyme based sensors, degradation, and poisoning. Electrodes that rely on the enzymatic (glucose oxidase) oxidation of glucose and subsequent conversion to electric current, are presently used in commercial sensors, including CGMS Gold™ (Medtronic Minimed™), Seven™(DexCom™), and Navigator™ (Abbott™/Therasense™), with FDA approval limited to one week use. While some of these challenges can be addressed by incorporating catalase, and while such electrodes represent a step forward in diabetes management, practical challenges remain, including the need for frequent (often daily) calibration against blood glucose obtained by finger-prick procedures.
Continuous Glucose Monitors (CGMs) can provide better management of glucose level. It is important for diabetic patient to identify fluctuations and trends in their glucose levels. This reduces the probability of emergency situations (e.g., hypoglycemic episodes, indicated by shaking, sweating, fast heartbeat, and impaired vision), particularly if monitoring is performed autonomously. However, current continuous glucose monitors have a number of disadvantages. They puncture the skin, need to be periodically replaced (as often as every week) and calibrated (as often as every 12 hours), restrict motion, are not waterproof (some can tolerate water but few or none can survive hot water), and are expensive.
Recently, an implantable glucose oxidase/catalase-based sensor was shown to reliably monitor glucose fluctuations in diabetic pigs for more than one year. In this disk-shaped system (diameter 3.4 cm, thickness 1.5 cm), the enzyme electrode was packaged with a battery and microelectronics for radiotelemetry. The sensor, implanted into tissue, exhibited short, 6-10 min “dynamic delays”, i.e. latencies in tracking up- and downswings in blood glucose concentration. Delays were attributed primarily to mass transfer in tissue. Also important was the demonstration of stable tissue encapsulation, with adequate capillary supply.
Glucose can be “sampled” by reverse iontophoresis across the skin and analyzed electrochemically. Glucowatch™, a product based on this concept, received FDA approval, but was withdrawn from the market due to skips in intermittent (20 min duty cycle) measurements and the need for daily calibration. Ultrasound followed by vacuum extraction across the skin and electrochemical detection, has also been proposed.
Blood glucose sensing by absorption and reflectance of near- and far-IR radiation, or by surface-enhanced Raman scattering (SERS), is under investigation. These optical techniques, while attractive since electromagnetic (EM) energy can be generated and sensed noninvasively, exhibit difficulties in establishing unambiguous correlation between signal and true blood glucose level due to interfering analytes and scattering by intervening tissues. They also require sophisticated, bulky, and expensive readout instrumentation.
In addition to glucose monitoring, detecting environmental changes, specifically chemical changes, has also received significant attention over the past few decades. Some of the sensors for detecting chemical changes are part of complex industrial systems.
There is, therefore, a continuing need for a simple system that allows detection of chemical environmental changes, and that overcomes challenges accompanied with present systems including the transcutaneous glucose electrodes and other systems described above. Continuous or substantially continuous monitoring can provide data that can be recorded, stored, locally analyzed, communicated over a network, studied for trends over time, and be used in a system with a feedback path to provide corrective actions when needed.
Continuous sensing, in conjunction with predictive algorithms, can improve guidance of these corrective actions to minimize episodes associated with conditions outside of normal ranges. The advantage of continuous monitoring may extend to Type II diabetes. Here, continuous monitoring of glucose concentration in the body can help physicians and patients evaluate pharmacologic and/or behavioral therapies.